1. The Case for a Threshold Bennett S
The Case for a Threshold Bennett S. Greenspan, MD, MS, FACNM, FACR, FSNMMI, FAAPM Immediate Past President, SNMMI ANS & HPS Applicability of Radiation Response Models to Low Dose Protection Standards Tri-Cities, Washington October 2, 2018

2. Disclosure
I do not have a financial interest, arrangement or affiliation, including receipt of honoraria or expenses from a commercial organization, that could have a direct impact in the subject matter of my presentation.

3. Case for a Threshold – LNT is Wrong
Linear No-Threshold hypothesis (LNT) is wrong
1. LNT claims cancer risk extends down to zero. But there has never been evidence to show increased risk below 100 mSv (10 rem) and probably 200 mSv (20 rem).
2. Whether or not low-dose damage is linearly proportional to dose, the defense response is nonlinear. DNA repair involves >150 genes, antioxidant production, apoptosis, bystander effects, and immune system response.
3. LNT excludes evolutionary biology. There are differing responses to high-dose vs. low-dose exposure.

4. Case for a Threshold – LNT is Wrong
4. LNT assumes radiation damage and associated cancer risk accumulate throughout life. – Not true, as this ignores repair of DNA damage as well as cellular turnover and elimination. 5. LNT assumes radiation induced-risk is independent of dose rate. Not true – radiation therapy is based on different responses due to different dose rates. 6. LNT assumes a single mutation will lead to cancer. – Not true. Development of malignancy requires multiple mutations and deficiencies of the body’s defense mechanisms as well as immune system failure. 7. No evidence of harm with higher background rates, up to at least 260 mSv (26 rem).

5. Case for a Threshold – Radiation Hormesis
Radiation hormesis is real
Many substances - drugs, vitamins, trace metals, are beneficial at low levels but toxic at high levels
Atom bomb survivors – exposures at Sv ( rem) – less nonmalignant disease; Leukemia – hormesis with threshold of 500 mSv (50 rem)
Cancer risk is below baseline at approximately 0.15 Gy weighted colon dose

6. Case for a Threshold - Hormesis
Fluoroscopy of Canadian TB patients with doses of mGy (5-30 rad) – 1/3 less breast cancer
Fluoroscopy of Massachusetts TB patients (mean dose Gy [ rem]) had markedly less mortality from lung cancer, compared to unexposed controls. However, breast cancer was increased (mean dose Gy [54-96 rem]) Ref: Davis, et al, Cancer Research 49: , 1989

7. Case for a Threshold - Hormesis
Protracted exposure of low level radiation <2 Gy (200 rem) does not increase risk of lung cancer.
The natural incidence of lung cancer is actually reduced.
Ref: Rossi, Zaider, Radiat Environ Biophys 1997 Jun;36(2):85-88

8. Case for a Threshold - Hormesis
Nuclear power workers (over 400,000, 154 facilities, 15 countries) decreased risk of malignancy
Mayak incident – individuals with exposures of 0.04, 0.12 and 0.5 Sv (4, 12 and 50 rem) – less cancer than individuals not exposed. At 0.5 mSv (50 rem) cancer mortality was 29% less than controls
Over 7200 Taiwan apt dwellers exposed to 48 mSv – fewer cancers than unexposed controls

9. Case for a Threshold - Hormesis
Radiation hormesis is real
Chronic exposure to low dose ionizing radiation induces DNA damage response, accumulated DNA damage only occurred in more highly exposed subjects; => suggestive of radiation hormesis. Ref: Gaetani et al. Occup Environ Med 2018 doi: /oemed
Derived standardized mortality rates for cancer and circulatory disease in French nuclear works are <1, suggestive of hormetic effects/adaptive response Ref: Scott B Dose Response 2018 Apr-Jun; 16(2): online 2018 May 28. doi: /

10. Case for a Threshold Thresholds
Everything has a threshold – drugs, vitamins, trace metals, other chemicals
Radiation is a natural entity of the environment, why should radiation be different?
Low dose radiation is beneficial, and high dose is harmful, there must exist a threshold between them.

11. Case for a Threshold Known thresholds for deterministic effects
Cumulative dose Gy
Pancytopenia
Sterility, men (temporary) 15
Sterility, women
Cataracts
Ref: Sanders 2017

12. Case for a Threshold Non-human data –
Beagle dogs that inhaled plutonium dioxide – threshold of approximately mSv (15-40 rem) Ref: Fisher and Weller, Health Phys. 99(3): , 2010
Mutations in fruit flies – threshold of 500 mGy (50 rad). Mutation rate similar to unexposed fruit flies.

13. Case for a Threshold
Ref: Fisher and Weller, Health Phys. 99(3): , 2010

14. Case for a Threshold
Courtesy of Mohan Doss

15. Case for a Threshold Thresholds for carcinogenesis
Transformation of human fibroblasts – threshold of approximately 20 rem
Secondary cancers following radiation therapy – latent period minimum approximately 5-8 years, threshold at least Gy ( rem), it may be as high as 5 Gy (500 rem)

16. Neoplastic transformation of human fibroblasts dips below bkgd frequency at low doses Ko et al, 2006

17. Case for a Threshold
Courtesy of Mohan Doss

18. Case for a Threshold/Hormesis
Thresholds for carcinogenesis
Nuclear power workers – no increase in mortality
Nuclear shipyard workers – 8 mSv (800 mrem) – 24% lower mortality
Plutonium workers (Manhattan Project) – decreased cancer incidence and mortality

19. Case for a Threshold
Atom bomb survivor data – threshold of up to approximately 700 mSv (70 rem)
Ref: Doss Dose Response 2013 Nov; 11(4):
Atom bomb survivors – threshold for solid cancers approximately 200 mSv (20 rem) Ref: Ozasa, 2012, 2013

20. Case for a Threshold
Ref: Ozasa et al, 2012, 2013

21. Case for a Threshold
Ref: Ozasa et al, 2012, 2013

22. ERR for all solid cancer mortality in atom bomb survivors
Doss Dose Response 2013

23. Case for a Threshold
People who live in high background areas – no increase in cancer rate. In some areas, rates are lower.
Fluoroscopy of Canadian TB patients – no increase in breast cancer below 550 mGy (55 rem)
Hyperthyroid patients treated with I-131 – no increased risk of thyroid cancer, other solid malignancies, or leukemia Ref: Saenger, et al, JAMA, 1968; 205(12):

24. Case for a Threshold
Courtesy of Mohan Doss

25. Case for a Threshold
Thyroid cancer patients treated with I-131 – no increase in solid tumors, slightly increased risk of leukemia above total administered activity of 600 mCi (22.2 GBq)
Radium dial painters – no increased risk of osteogenic sarcoma below 10 Gy (1000 rad)

26. Case for a Threshold
Threshold: radium dial painters

27. Case for a Threshold Conclusions:
General principles – behavior of radiation as a toxic substance is similar to other toxic substances
Low dose radiation is beneficial, and high dose is harmful, therefore a threshold between them must exist.
Thresholds for deterministic effects are known.

28. Case for a Threshold Conclusions, continued:
Thresholds for development of carcinogenesis are identified.
Different tumors exhibit different thresholds.
Thresholds in humans probably range from (0.15 – 0.70 mSv (15 – 70 rem).
It appears reasonable that all low dose radiation effects have a threshold.